Margolis F L, Verhaagen J, Biffo S, Huang F L, Grillo M
Department of Neurosciences, Roche Institute of Molecular Biology, Nutley, NJ 07110.
Prog Brain Res. 1991;89:97-122. doi: 10.1016/s0079-6123(08)61718-5.
The olfactory neuroepithelium exhibits neurogenesis throughout adult life, and in response to lesions, a phenomenon that distinguishes this neural tissue from the rest of the mammalian brain. The newly formed primary olfactory neurons elaborate axons into the olfactory bulb. Thus, denervation and subsequent reinnervation of olfactory bulb neurons may occur throughout life. This unique ability of the olfactory neuroepithelium to generate new neurons from a population of precursor cells present in the basal cell layer of this tissue makes it a valuable model in the study of neural development and regeneration. The molecular processes underlying the neurogenic properties of the olfactory neuroepithelium are poorly understood. Here we have reviewed our studies on the expression of B50/GAP43 during ontogeny of the olfactory system and following lesioning. This analysis includes the characterization of the expression of OMP, a protein expressed in mature olfactory neurons, as well as PKC and calmodulin. The latter two molecules are of particular interest to the function of B50/GAP43 since the degree of phosphorylation of B50/GAP43 appears to determine B50/GAP43's ability to bind calmodulin (see also Storm, chapter 4, this volume). In the mature olfactory epithelium B50/GAP43 expression is restricted to a subset of cells located in the basal region. Since the expression of B50/GAP43 is high in developing and regenerating nerve cells we are confident that the B50/GAP43 positive cells are new neurons derived from the stem cells in the basal region of the epithelium. B50/GAP43 is absent from the stem cells themselves and also from the mature OMP-expressing neurons. On the basis of the patterns of B50/GAP43 and OMP expression two stages could be discriminated in the regeneration of the olfactory epithelium. First, as an immediate response to lesioning a large population of B50/GAP43 positive, OMP negative neurons are formed. Subsequently, during the second stage, these newly formed differentiating neurons mature as evidenced by a decrease in B50/GAP43 and an increase in OMP expression. The second stage in the regeneration process is only manifested if the regenerating neurons can reach their target cells in the olfactory bulb. Hence, bulbectomy results in the arrest of the reconstituted olfactory epithelium in an immature state. The differential patterns of B50/GAP43 expression following peripheral lesioning and bulbectomy suggest the existence of a target derived signal molecule involved in the down-regulation of B50/GAP43 expression in olfactory neurons that have established synaptic contacts in the olfactory bulb (see also Willard, chapter 2, this volume, "the suppressor hypothesis").(ABSTRACT TRUNCATED AT 400 WORDS)
嗅觉神经上皮在成年期全程都表现出神经发生现象，并且在受到损伤时也会如此，这一现象将这种神经组织与哺乳动物大脑的其他部分区分开来。新形成的初级嗅觉神经元会延伸轴突进入嗅球。因此，嗅球神经元的去神经支配和随后的再支配可能在一生中都会发生。嗅觉神经上皮从该组织基底细胞层中存在的一群前体细胞产生新神经元的这种独特能力，使其成为神经发育和再生研究中的一个有价值的模型。嗅觉神经上皮神经源性特性背后的分子过程目前了解甚少。在此，我们回顾了我们关于嗅觉系统个体发育期间以及损伤后B50/GAP43表达的研究。该分析包括对OMP（一种在成熟嗅觉神经元中表达的蛋白质）以及蛋白激酶C和钙调蛋白表达特征的研究。后两种分子对于B50/GAP43的功能特别重要，因为B50/GAP43的磷酸化程度似乎决定了其结合钙调蛋白的能力（另见本卷第4章斯托姆的内容）。在成熟的嗅觉上皮中，B50/GAP43的表达仅限于位于基底区域的一部分细胞。由于B50/GAP43在发育中和再生的神经细胞中表达较高，我们确信B50/GAP43阳性细胞是源自上皮基底区域干细胞的新神经元。B50/GAP43在干细胞自身以及成熟的表达OMP的神经元中均不存在。基于B50/GAP43和OMP的表达模式，可以区分嗅觉上皮再生的两个阶段。首先，作为对损伤的即时反应，会形成大量B
